In addition to their roles in transcription, growth and proliferation, and retroviral integration, emerging evidence implicates the High Mobility Group A1 (HMGA1) proteins as important mediators in oncogenic transformation. Enforced expression of HMGA1 leads to neoplastic transformation in vitro and in vitro, potentially explaining the worsened outcomes observed in patients expressing the proteins. Although several putative target genes of HMGA1a have been identified, the exact pathways for malignant transformation by HMGA1a are not clearly understood. The PI's long-term goal is to understand the strikingly complex molecular networks surrounding HMGA1a-associated neoplasia. To this end, this proposal aims to conduct a detailed and systematic structure-function study of transformation and apoptosis induced by HMGA1a. The PI and her undergraduates have obtained preliminary data that indicates that the understudied third A/T hook (AT hook III) domain of the protein contributes to the protein's oncogenic activity. In addition, we will further dissect the role of individual amino acids within the regions required for oncogenic potential. Potential sites of evaluation are those important for transcriptional regulation and sites of posttranslational methylation. The proposed experiments will employ genetic and biochemical techniques to identify the domains of HMGA1a that are involved in propagating signals that lead to its transforming potential. Very little is known about the regions of HMGA1 required for its oncogenic activity so we will conduct structure function studies by measuring changes in soft agar transformation, apoptosis induction, and DNA binding as a result of deletion and point mutations. Over the three year project period, the PI and as many as 10 undergraduates in independent research will collaboratively accomplish the major objectives of the AREA program: (1) supporting meritorious research, (2) exposing undergraduates to research, and (3) stimulating the research environment in primarily undergraduate institutions that have not been major recipients of NIH funding. Understanding the mechanisms of HMGA1a- associated cancers will not only contribute to efforts aimed at preempting cancer at the earliest stages of its progression but will also expose promising undergraduate to meritorious biomedical research and strengthen the research environment in a non-research intensive university. PUBLIC HEALTH RELEVANCE: The proposed research aims to understand the specific molecular events associated with cancer initiation and progression involving a class of proteins that are increased in several cancer types. These and other studies will provide the information needed to design specific and effective drug therapies for cancer treatment.